Resolving agents, racemate chiral resolution, crystallization

The most classical of resolutions is exemplified by the separation, by crystallization, of the diastereomeric salts formed by treatment of a racemic acid with one enantiomer of a chiral base, typically an alkaloid such as quinine. Unfortunately, despite significant recent advances (3,6), the relative solubilities of two diastereomers, and thus the probability for success of a classical resolution, are difficult to predict. It thus remains, for most chemists, a largely empirical method. On the other hand, a successful resolution often provides both enantiomers, even when both enantiomers of the resolving agent are not at hand, by recovery from the enriched... 

Resolution of racemic mixtures using a chiral resolving agent is based on the formation of two diastereoisomeric entities, usually salts differing in their solubility, leading to preferential crystallization of one of them (Figure 13.3). The chemical nature of the racemate usually defines the compatible chemical character of the... 

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

However, during the purification of enantiomeric mixtures (having diastereoisomeric relationship and -behaviour of the homo- and heterochiral aggregates) both the kinetic and thermodynamic control can be observed, and certainly these phenomena can be observed at the (re)crystallization of diastereoisomers as well. At the same time in case of reciprocal resolution (one of the enantiomers of the original racemic compound is applied as resolving agent for resolution of the racemic mixture of the initial chiral agent) the former behaviour is expected inevitably (namely the previously experienced kinetic- or thermodynamic control can be observed). 

When the racemic acid or base is treated with less than an equivalent amount of chiral compound (resolving agent) one can obtain a good enantiomer separation if crystallization occures in the mixture. For example, at the resolution of racemic ibuprofen (TBU) with (R)-PEA, the free enantiomer (S)-IBU can be separated from the salt ((R)-IBU.(R)-PEA) by extraction with a supercritical fluid, most often with carbon dioxide ... 

Resolution of racemates through the diastereomer formation and selective crystallization is a common strategy for chemical separation of enantiomers from racemic mixtures employing chiral resolving agents. The principle of a... 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

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